Prevalence and Risk Factors of Premature Ovarian Insufficiency/Early Menopause

Premature ovarian insufficiency (POI) and early menopause, defined as loss of ovarian activity prior to 40 years or menopause between the ages of 40 and 45 years, respectively, is associated with significant adverse health impacts. Recent data indicate that the prevalence of POI and early menopause is greater than was previously thought, affecting more than 10% of women. Biopsychosocial risk factors including genetic, autoimmune, reproductive, lifestyle, early-life, social/environmental, and iatrogenic have been associated with POI/early menopause or earlier age at menopause. However, establishing a causal role and the underlying mechanisms remains elusive. Understanding and clarification of these risk factors will facilitate prevention and risk minimization strategies to optimize women's health. Publication History Article published online: 12 January 2021 © 2020. Thieme. All rights reserved. Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA -

- 1 Webber L, Davies M, Anderson R. et al; European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod 2016; 31 (05) 926-937 - 2 InterLACE Study Team. Variations in reproductive events across life: a pooled analysis of data from 505 147 women across 10 countries. Hum Reprod 2019; 34 (05) 881-893 - 3 Xu X, Jones M, Mishra GD. Age at natural menopause and development of chronic conditions and multimorbidity: results from an Australian prospective cohort. Hum Reprod 2020; 35 (01) 203-211 - 4 Anagnostis P, Siolos P, Gkekas NK. et al. Association between age at menopause and fracture risk: a systematic review and meta-analysis. Endocrine 2019; 63 (02) 213-224 - 5 Anagnostis P, Christou K, Artzouchaltzi AM. et al. Early menopause and premature ovarian insufficiency are associated with increased risk of type 2 diabetes: a systematic review and meta-analysis. Eur J Endocrinol 2019; 180 (01) 41-50 - 6 Zhu D, Chung HF, Dobson AJ. et al. Age at natural menopause and risk of incident cardiovascular disease: a pooled analysis of individual patient data. Lancet Public Health 2019; 4 (11) e553-e564 - 7 Muka T, Oliver-Williams C, Kunutsor S. et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol 2016; 1 (07) 767-776 - 8 Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 2015; 18 (04) 483-491 - 9 Gong D, Sun J, Zhou Y, Zou C, Fan Y. Early age at natural menopause and risk of cardiovascular and all-cause mortality: a meta-analysis of prospective observational studies. Int J Cardiol 2016; 203: 115-119 - 10 Gargus E, Deans R, Anazodo A, Woodruff TK. Management of primary ovarian insufficiency symptoms in survivors of childhood and adolescent cancer. J Natl Compr Canc Netw 2018; 16 (09) 1137-1149 - 11 Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986; 67 (04) 604-606 - 12 Mishra GD, Chung H-F, Cano A. et al. EMAS position statement: predictors of premature and early natural menopause. Maturitas 2019; 123: 82-88 - 13 Golezar S, Ramezani Tehrani F, Khazaei S, Ebadi A, Keshavarz Z. The global prevalence of primary ovarian insufficiency and early menopause: a meta-analysis. Climacteric 2019; 22 (04) 403-411 - 14 Chemaitilly W, Li Z, Krasin MJ. et al. Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude Lifetime cohort. J Clin Endocrinol Metab 2017; 102 (07) 2242-2250 - 15 Janse F, Knauff EA, Niermeijer MF. et al; Dutch Premature Ovarian Failure Consortium. Similar phenotype characteristics comparing familial and sporadic premature ovarian failure. Menopause 2010; 17 (04) 758-765 - 16 Luborsky JL, Meyer P, Sowers MF, Gold EB, Santoro N. Premature menopause in a multi-ethnic population study of the menopause transition. Hum Reprod 2003; 18 (01) 199-206 - 17 Chang SH, Kim CS, Lee KS. et al. Premenopausal factors influencing premature ovarian failure and early menopause. Maturitas 2007; 58 (01) 19-30 - 18 Jungari SB, Chauhan BG. Prevalence and determinants of premature menopause among Indian women: issues and challenges ahead. Health Soc Work 2017; 42 (02) 79-86 - 19 Choe SA, Sung J. Trends of premature and early menopause: a comparative study of the US National Health and Nutrition Examination Survey and the Korea National Health and Nutrition Examination Survey. J Korean Med Sci 2020; 35 (14) e97 - 20 Schoenaker DA, Jackson CA, Rowlands JV, Mishra GD. Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents. Int J Epidemiol 2014; 43 (05) 1542-1562 - 21 Ding X, Tang R, Zhu J. et al. An appraisal of the role of previously reported risk factors in the age at menopause using mendelian randomization. Front Genet 2020; 11 (507) 507 - 22 Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update 2015; 21 (06) 787-808 - 23 Gravholt CH, Andersen NH, Conway GS. et al; International Turner Syndrome Consensus Group. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017; 177 (03) G1-G70 - 24 Persani L, Rossetti R, Cacciatore C, Bonomi M. Primary Ovarian Insufficiency: X chromosome defects and autoimmunity. J Autoimmun 2009; 33 (01) 35-41 - 25 Murray A, Bennett CE, Perry JR. et al; ReproGen Consortium. Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study. Hum Mol Genet 2011; 20 (01) 186-192 - 26 Fridovich-Keil JL, Gubbels CS, Spencer JB, Sanders RD, Land JA, Rubio-Gozalbo E. Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis 2011; 34 (02) 357-366 - 27 Perry JR, Corre T, Esko T. et al; ReproGen Consortium. A genome-wide association study of early menopause and the combined impact of identified variants. Hum Mol Genet 2013; 22 (07) 1465-1472 - 28 He C, Kraft P, Chen C. et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet 2009; 41 (06) 724-728 - 29 Morris DH, Jones ME, Schoemaker MJ, Ashworth A, Swerdlow AJ. Familial concordance for age at natural menopause: results from the Breakthrough Generations Study. Menopause 2011; 18 (09) 956-961 - 30 van Asselt KM, Kok HS, Pearson PL. et al. Heritability of menopausal age in mothers and daughters. Fertil Steril 2004; 82 (05) 1348-1351 - 31 Murabito JM, Yang Q, Fox C, Wilson PW, Cupples LA. Heritability of age at natural menopause in the Framingham Heart Study. J Clin Endocrinol Metab 2005; 90 (06) 3427-3430 - 32 Treloar SA, Do KA, Martin NG. Genetic influences on the age at menopause. Lancet 1998; 352 (9134): 1084-1085 - 33 Snieder H, MacGregor AJ, Spector TD. Genes control the cessation of a woman's reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab 1998; 83 (06) 1875-1880 - 34 de Bruin JP, Bovenhuis H, van Noord PA. et al. The role of genetic factors in age at natural menopause. Hum Reprod 2001; 16 (09) 2014-2018 - 35 Cramer DW, Xu H, Harlow BL. Family history as a predictor of early menopause. Fertil Steril 1995; 64 (04) 740-745 - 36 Kirshenbaum M, Orvieto R. Premature ovarian insufficiency (POI) and autoimmunity-an update appraisal. J Assist Reprod Genet 2019; 36 (11) 2207-2215 - 37 La Marca A, Brozzetti A, Sighinolfi G, Marzotti S, Volpe A, Falorni A. Primary ovarian insufficiency: autoimmune causes. Curr Opin Obstet Gynecol 2010; 22 (04) 277-282 - 38 Kahaly GJ, Frommer L. Polyglandular autoimmune syndromes. J Endocrinol Invest 2018; 41 (01) 91-98 - 39 Gosden RG, Treloar SA, Martin NG. et al. Prevalence of premature ovarian failure in monozygotic and dizygotic twins. Hum Reprod 2007; 22 (02) 610-615 - 40 Ruth KS, Perry JR, Henley WE, Melzer D, Weedon MN, Murray A. Events in early life are associated with female reproductive ageing: a UK Biobank study. Sci Rep 2016; 6: 24710 - 41 Sadrzadeh S, Verschuuren M, Schoonmade LJ, Lambalk CB, Painter RC. The effect of adverse intrauterine conditions, early childhood growth and famine exposure on age at menopause: a systematic review. J Dev Orig Health Dis 2018; 9 (02) 127-136 - 42 Goldberg M, Tawfik H, Kline J. et al. Body size at birth, early-life growth and the timing of the menopausal transition and natural menopause. Reprod Toxicol 2020; 92: 91-97 - 43 Mishra G, Hardy R, Kuh D. Are the effects of risk factors for timing of menopause modified by age? Results from a British birth cohort study. Menopause 2007; 14 (04) 717-724 - 44 Langton CR, Whitcomb BW, Purdue-Smithe AC. et al. Association of parity and breastfeeding with risk of early natural menopause. JAMA Netw Open 2020; 3 (01) e1919615 - 45 Kuh D, Butterworth S, Kok H. et al. Childhood cognitive ability and age at menopause: evidence from two cohort studies. Menopause 2005; 12 (04) 475-482 - 46 Whalley LJ, Fox HC, Starr JM, Deary IJ. Age at natural menopause and cognition. Maturitas 2004; 49 (02) 148-156 - 47 Magnus MC, Anderson EL, Howe LD, Joinson CJ, Penton-Voak IS, Fraser A. Childhood psychosocial adversity and female reproductive timing: a cohort study of the ALSPAC mothers. J Epidemiol Community Health 2018; 72 (01) 34-40 - 48 Hardy R, Kuh D. Social and environmental conditions across the life course and age at menopause in a British birth cohort study. BJOG 2005; 112 (03) 346-354 - 49 Mishra GD, Cooper R, Tom SE, Kuh D. Early life circumstances and their impact on menarche and menopause. Womens Health (Lond) 2009; 5 (02) 175-190 - 50 Demakakos P, Pashayan N, Chrousos G, Linara-Demakakou E, Mishra GD. Childhood experiences of parenting and age at menarche, age at menopause and duration of reproductive lifespan: evidence from the English Longitudinal Study of Ageing. Maturitas 2019; 122: 66-72 - 51 Mishra GD, Pandeya N, Dobson AJ. et al. Early menarche, nulliparity and the risk for premature and early natural menopause. Hum Reprod 2017; 32 (03) 679-686 - 52 Whitcomb BW, Purdue-Smithe A, Hankinson SE, Manson JE, Rosner BA, Bertone-Johnson ER. Menstrual cycle characteristics in adolescence and early adulthood are associated with risk of early natural menopause. J Clin Endocrinol Metab 2018; 103 (10) 3909-3918 - 53 Wang H, Chen H, Qin Y. et al. Risks associated with premature ovarian failure in Han Chinese women. Reprod Biomed Online 2015; 30 (04) 401-407 - 54 Roman Lay AA, do Nascimento CF, Horta BL, Dias Porto Chiavegatto Filho A. Reproductive factors and age at natural menopause: a systematic review and meta-analysis. Maturitas 2020; 131: 57-64 - 55 de Angelis C, Nardone A, Garifalos F. et al. Smoke, alcohol and drug addiction and female fertility. Reprod Biol Endocrinol 2020; 18 (01) 21 - 56 Blanck HM, Marcus M, Tolbert PE. et al. Time to menopause in relation to PBBs, PCBs, and smoking. Maturitas 2004; 49 (02) 97-106 - 57 Zhu D, Chung H-F, Pandeya N. et al. Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: a pooled analysis of individual data from 17 observational studies. PLoS Med 2018; 15 (11) e1002704-e1002704 - 58 Whitcomb BW, Purdue-Smithe AC, Szegda KL. et al. Cigarette smoking and risk of early natural menopause. Am J Epidemiol 2018; 187 (04) 696-704 - 59 Zhu D, Chung H-F, Pandeya N. et al. Body mass index and age at natural menopause: an international pooled analysis of 11 prospective studies. Eur J Epidemiol 2018; 33 (08) 699-710 - 60 Tao X, Jiang A, Yin L, Li Y, Tao F, Hu H. Body mass index and age at natural menopause: a meta-analysis. Menopause 2015; 22 (04) 469-474 - 61 Szegda KL, Whitcomb BW, Purdue-Smithe AC. et al. Adult adiposity and risk of early menopause. Hum Reprod 2017; 32 (12) 2522-2531 - 62 Zhao M, Whitcomb BW, Purdue-Smithe AC. et al. Physical activity is not related to risk of early menopause in a large prospective study. Hum Reprod 2018; 33 (10) 1960-1967 - 63 Gold EB, Crawford SL, Avis NE. et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol 2013; 178 (01) 70-83 - 64 Mikkelsen TF, Graff-Iversen S, Sundby J, Bjertness E. Early menopause, association with tobacco smoking, coffee consumption and other lifestyle factors: a cross-sectional study. BMC Public Health 2007; 7: 149 - 65 Purdue-Smithe AC, Whitcomb BW, Manson JE. et al. Vitamin D status is not associated with risk of early menopause. J Nutr 2018; 148 (09) 1445-1452 - 66 Taneri PE, Kiefte-de Jong JC, Bramer WM, Daan NM, Franco OH, Muka T. Association of alcohol consumption with the onset of natural menopause: a systematic review and meta-analysis. Hum Reprod Update 2016; 22 (04) 516-528 - 67 Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update 2005; 11 (04) 391-410 - 68 Imai K, Sutton MY, Mdodo R, Del Rio C. HIV and menopause: a systematic review of the effects of HIV infection on age at menopause and the effects of menopause on response to antiretroviral therapy. Obstet Gynecol Int 2013; 2013: 340309 - 69 Vabre P, Gatimel N, Moreau J. et al. Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data. Environ Health 2017; 16 (01) 37 - 70 Gallicchio L, Miller S, Greene T, Zacur H, Flaws JA. Premature ovarian failure among hairdressers. Hum Reprod 2009; 24 (10) 2636-2641 - 71 Pan W, Ye X, Yin S. et al. Selected persistent organic pollutants associated with the risk of primary ovarian insufficiency in women. Environ Int 2019; 129: 51-58 - 72 Grindler NM, Allsworth JE, Macones GA, Kannan K, Roehl KA, Cooper AR. Persistent organic pollutants and early menopause in U.S. women. PLoS One 2015; 10 (01) e0116057 - 73 Ding N, Harlow SD, Randolph JF. et al. Associations of perfluoroalkyl substances with incident natural menopause: the study of women's health across the nation. J Clin Endocrinol Metab 2020; 105 (09) dgaa303 - 74 Spears N, Lopes F, Stefansdottir A. et al. Ovarian damage from chemotherapy and current approaches to its protection. Hum Reprod Update 2019; 25 (06) 673-693 - 75 Thomas-Teinturier C, El Fayech C, Oberlin O. et al. Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature. Hum Reprod 2013; 28 (02) 488-495 - 76 Zavos A, Valachis A. Risk of chemotherapy-induced amenorrhea in patients with breast cancer: a systematic review and meta-analysis. Acta Oncol 2016; 55 (06) 664-670 - 77 Zhao J, Liu J, Chen K. et al. What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis. Breast Cancer Res Treat 2014; 145 (01) 113-128 - 78 Chen H, Xiao L, Li J, Cui L, Huang W. Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in premenopausal women. Cochrane Database Syst Rev 2019; 3: CD008018 - 79 Raffi F, Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012; 97 (09) 3146-3154 - 80 Busacca M, Riparini J, Somigliana E. et al. Postsurgical ovarian failure after laparoscopic excision of bilateral endometriomas. Am J Obstet Gynecol 2006; 195 (02) 421-425 - 81 Coccia ME, Rizzello F, Mariani G, Bulletti C, Palagiano A, Scarselli G. Ovarian surgery for bilateral endometriomas influences age at menopause. Hum Reprod 2011; 26 (11) 3000-3007